If researchers knew more—even if they could pin autism’s roots to a region of the brain—then they could focus on finding treatments that relieve or prevent it. For Newschaffer, that hope is personal. He has a 12-year-old son who has autism, and his experience as the father of an autistic child helped convince him to focus his epidemiological research on the disorder.

“We always like to point to home runs,” Newschaffer says of his profession. He notes one “homer” that epidemiologists are particularly proud of: making the link between a lack of folic acid in a woman’s diet and the resulting neural tube defect in her offspring. Women are now advised to take folic acid before and during pregnancy to reduce their risk of having a child with a neural tube defect by as much as 70 percent.

Before he was 2, John Gillin could count to 20 in English and in Spanish. He counted so much, his family called him “The Count” after the Sesame Street character. Then things changed.

Autism research is unlikely to yield such a home run. Because so many different genes—possibly in combination with various environmental factors—may cause autism, researchers would be happy to get a base hit. When Andrew Zimmerman, a pediatric neurologist and CADDE co-investigator, announced that he was going to study the underpinnings of autism, an older faculty member who had had a successful career investigating a disorder caused by a single gene tried to dissuade him. “Why do you want to get into that swamp?” he asked. But Zimmerman was determined. He had seen the full spectrum of the illness. Alex Bush and John Gillin are both his patients.

It’s Christmas Day, 1995, in a house in Cockeysville, Maryland. A toddler with dark eyes and dark hair wearing red sleeper pajamas excitedly plunges his hand into an enormous stocking, pulls out a package and unwraps it. “A big new ball!” he exclaims. “I want to play catch!” He tucks the small ball safely under one arm while he hunts for more presents, issuing a steady stream of commentary about each gift.

The boy is Alex Bush, as he appears in a videotape his parents recorded in their former home when their son was 2. Then, Alex spoke in complete sentences. He knew the words to “Jesus Loves Me” and could sing a funny song about bubbles. Already sharing the family’s passion for baseball, he could recite the names of some of the Baltimore Orioles.

But that was about as far as Alex ever got in learning to speak. Fast-forward the video to a clip taken a few months later. Alex and his sister Chelsea are tucked in bed listening to their mother read a book about baseball. Sandy Bush pauses frequently to ask her children questions about the story they have read dozens of times before. Alex answers his mother’s questions, but he is quieter than he was at Christmas, and he does not talk unless his mother asks him a question. Sometimes Sandy has to repeat the question.

The signs were subtle, but Alex was starting to withdraw and lose his ability to speak. Over the next few months, he spoke less and understood less. His parents took Alex to specialists, including Zimmerman at the Kennedy Krieger Institute, who diagnosed autism.

But such dramatic regression does not always occur in children with autism. For John Gillin, autism was less obvious and took longer to diagnose.

The signs were subtle at first with Alex Bush, but within a few months the garrulous toddler withdrew from others and stopped talking.

At 18 months, John seemed precocious in some ways. On a trip to Florida, his mom recalls, John kept saying, “Eight! Eight!” It baffled his parents until they realized their son was reading the numeral on their beach cabana. Before he was 2, John could count to 20 in English and Spanish, and knew his alphabet. He counted so much, his family called him “The Count,” after the Sesame Street character. By age 3, he had begun to read.

But something was not right. Although John knew a lot of words, he couldn’t put them together to form a sentence. He could say “cookie,” but not “I want a cookie.” The Gillins took their son to several specialists, eventually arriving at a diagnosis of autism.

“I think the heterogeneity of autism is one thing that has kept many researchers out of the field,” says Zimmerman.

Researchers and clinicians have been studying and debating the cause of this enigmatic disorder ever since Johns Hopkins child psychiatrist Leo Kanner first coined the term. In a paper published in 1943, Kanner described the cases of 11 children who were extremely socially withdrawn, lacked language skills and engaged in ritualized behaviors. Kanner proposed that these behaviors sprang from brain abnormalities present before birth. But his idea ended there; Kanner was never able to find a biological source for autism.

Then psychologists started developing their own theories, most famously the psychodynamic explanation popularized by Bruno Bettelheim. In his book The Empty Fortress, Bettelheim concluded that cold and emotionally distant parents (called “refrigerator mothers”) gave rise to autistic offspring by depriving their children of the emotional and social connections required for normal development.

Later, abandoning those theories for lack of evidence, scientists again contemplated the biological underpinnings of autism. Research began to suggest that autism had its roots in the development of the brain, and family and twin studies demonstrated that autism has a genetic component.

What is now becoming clear is that understanding this curious and puzzling disorder may require new “outside-the-box” scientific models.

30 to 60 children out of 10,000 are now estimated to have an autism spectrum disorder.

Zimmerman began thinking about autism in a different way in the mid-1980s, after he began an autism clinic at the University of Tennessee. While seeing dozens of patients with autism, Zimmerman also got to know his patients’ relatives. “Certain things would stand out,” he says. Many of the mothers themselves were ill, particularly with autoimmune diseases.

He conducted an epidemiological study that confirmed his observations. Mothers of his autistic patients were eight to nine times more likely than people in a control group to have rheumatoid arthritis. Since joining the Hopkins faculty in 1994, Zimmerman, along with epidemiologist Li-Ching Lee, an assistant scientist of Epidemiology, has reported that many of the mothers from Tennessee carry an antigen that frequently occurs in people with autoimmune disorders. These findings haveled Zimmerman to believe that the autism disorder may arise from a sort of autoimmune reaction.

“The fetus is something like a tissue transplant,” says Zimmerman. Normally (for reasons that remain a mystery to scientists) the mother’s immune system tolerates the fetus. Zimmerman is exploring the hypothesis that autism may result from failures in this mechanism. If the mother’s immune system reacts against the fetus, for instance, it might target the fetal brain. Such a reaction could fundamentally change connections among the brain’s cells or cause inflammation, possibly leading to autism.

In autopsy studies conducted with Hopkins neuropathologist Carlos Pardo, Zimmerman has found signs of the inflammation this model predicts. The team analyzed brain autopsies of nine autistic people, ranging in age from 6 to 55. Without exception, every one showed inflammation. Other researchers have found additional differences in the brains of people with autism—subtle changes in regions that develop during the second trimester. “To me, this is the most exciting thing I’ve seen in the field,” says Zimmerman.

Other researchers are studying variations on this theme, if other forms of incompatibilitybetween mother and fetus are linked to autism. For example, Newschaffer and genetic epidemiologist Peter Zandi, PhD, an assistant professor in the Bloomberg School’s Department of Mental Health, are studying whether maternal-fetal differences in Rh factor or blood type are linked to an increased risk of autism. (more)

Autism on the Rise?

CADDE director Craig Newschaffer with his son Jonas in 2002. Photo: Howard Korn

The caller was sure he knew why autism rates have escalated: homes being built with attached car garages. Pollutants in car exhaust were harming children's developing brains.

Craig Newschaffer, director of the Bloomberg School's Center for Autism and Developmental Disabilities Epidemiology (CADDE), has heard many explanations, but which theories are correct? And is there, in fact, an "autism epidemic"?With a scientist's precision, Newschaffer crafts a careful answer. "It's undeniable that there are more kids now with an autism diagnosis," he says. So, by definition, there is an epidemic of autism. "But 'epidemic' is a charged word," says Newschaffer. It implies that something new is going on; a virus or toxic chemical or other new risk factor is affecting more people.What could account for the increase? One possibility, posits Newschaffer: changes in the way autism is diagnosed.Since Leo Kanner described the first cases of autism in 1943, diagnosticians have introduced the concept of a spectrum of autism disorders. There are now six subgroups: pervasive developmental disorder (PDD), autistic disorder, pervasive developmental disorder not-otherwise-specified (PDD-NOS), Asperger's syndrome, child disintegrative disorder and Rett syndrome.While Kanner and his contemporaries believed autism affected only 3 of every 10,000 children, recent studies by the Centers for Disease Control and Prevention have shown that between 30 to 60 of every 10,000 children have an autism spectrum disorder.This shift in definition could have increased diagnoses of autism. So too could a greater awareness of autism on the part of clinicians. Some physicians may now be better at recognizing autism, especially the milder cases such as Asperger's syndrome, in which a child has normal cognitive abilities but has difficulty understanding nonverbal and emotional aspects of human interaction. "Trends may be changing behind the scenes," says Newschaffer. "Do I have the data to support it? Not yet."Some answers may come from two new CADDE studies. In one, CADDE and 14 other research centers are screening the data collected by schools and clinics on children who might need special education services. The researchers are recording the number of children who fit the current criteria for autism. They will then repeat the survey in subsequent years to see if the numbers shift.In the second study, Newschaffer and his colleagues are surveying pediatricians about how they screen for autism, what they do if they suspect a child has autism and whether they are more vigilant in searching for it. Newschaffer hopes future surveys will show whether trends are shifting. "I think a good chunk of the increase in autism may be changes in definition and diagnosis," says Newschaffer. But he entertains the possibility that other "new things" could explain a portion of the disorder's rise."Everybody wants there to be a magic bullet," says Newschaffer, a simple explanation for the increase in autism. The truth could be much more complicated. —Melissa Hendricks